“We may be able to use the new epigenetic mark, hydroxymethylation, for improved strategies for reprogramming any cell into a stem cell, and hence in regenerative medicine.” –Professor Wolf Reik.

Scientists from the Babraham Institute have gained a new understanding of how molecular signals and switches control how an embryo develops into an adult. The new research details how a newly discovered form of epigenetic regulation controls the development of embryonic stem (ES) cells.

The research, funded by the Biotechnology and Biological Sciences Research Council (BBSRC), the Medical Research Council (MRC), the University of Cambridge, and the EPIGENOME Network of Excellence, has important implications for regenerative medicine as it could offer new methods for controlling how ES cells differentiate in every cell in the human body and, potentially, to the growing field of induced pluripotent stem (iPS) cells where adult stem cell are ‘reprogrammed’.

ES cells are pluripotent cells present in the early embryo, which have the capacity to differentiate into all the specialized cells that make up the adult body. As an embryo develops, the cells respond to signals and differentiate to acquire a particular fate, for example a skin cell. Cell fate is governed not only by the genome, but also by chemical changes to DNA that alter the DNA structure but not its sequence. These ‘epigenetic’ tags are one of the ways that genes get switched on or off in different places at different times, enabling different tissues and organs to arise from a single fertilized egg and also help to explain how our genes can be influenced by the environment.

The new research reveals that a new type of epigenetic modification, 5-hydroxymethylcytosine (5hmC), plays a critical role mediating the external signals that instruct a cell how to develop; this tiny chemical tag (5hmC) is attached to or removed from the genetic sequence depending on the message received, switching genes on or off. The researchers managed to identify the location of this tag throughout the genome, using high throughput sequencing methods. They observed for so called pluripotency-related genes that, as 5hmC decreases, another previously known epigenetic modification, 5-methylcytosine (5mC), increases – this shift has consequences in determining how genes function and hence a cell’s developmental fate.

The pluripotency window for stem cells is short-lived but essential for the environment and pre-defined genetic program to exert influence on the direction that each cell should take to build a healthy embryo. Hydroxy-methylation appears to be linked to a higher degree of pluripotency; when the process of generating 5hmC tags in the stem cell genome was disrupted, the researchers saw the pluripotency–related genes were down-regulated, causing the cells to be more ‘receptive’ to signals that promote differentiation than would normally be the case for stem cells.

The two epigenetic modifications, 5mC and 5hmC, were seen to have other opposing behavior in the genome, which might be important for maintaining flexibility of stem cells in order to respond accurately to external cues.

Knowing how hydroxymethylation works in embryonic stem cells might also help with reprogramming adult cells into induced pluripotent stem cells (iPS cells), since removal of methylation is important in generating these cells. Hence increasing the amounts of hydroxymethylation during reprogramming might make the process more efficient and error-free. This might help with developing improved strategies for regenerative medicine.

Professor Wolf Reik (pictured), who led the study at the Babraham Institute, which receives strategic funding from the BBSRC said, “This work provides an exciting new perspective on what makes embryonic stem cells special. It shows how the balance between opposing epigenetic marks is important for the ability of stem cells to differentiate into different tissues. We may be able to use the new epigenetic mark, hydroxymethylation, for improved strategies for reprogramming any cell into a stem cell, and hence in regenerative medicine.”

While advancing our understanding of the biology behind ‘reprogramming’, these findings may also help to explain how epigenetic changes occurring during ageing can cause disease, since conditions like heart disease and autoimmune disorders may be associated with failure of epigenetic regulation. It is known that 5hmC is most abundant in ES cells and in the brain. This study opens up many questions on the role that 5hmC may play in a non-dividing brain cell, modulating gene expression, and its relationship with memory formation and neurological disorders. Gabriella Ficz, joint lead author of this research said, “Our work reveals important aspects about the epigenetics of stem cells but looking at our data I couldn’t stop wondering about the involvement of this new modification in ageing and complex diseases like diabetes, autoimmune disorders, and schizophrenia as well as cancer and obesity. It is an exciting time for epigenetic research!”

Miguel R. Branco, joint lead author commented, “The recent discovery of this new DNA modification has attracted a quickly growing interest from the scientific community. Whilst it is still early days and we will have to dig deeper to better understand its role, our work has unveiled important links between hydroxymethylation, methylation, and the regulation of pluripotency genes.”

Professor Douglas Kell, BBSRC Chief Executive, said, “Fundamental biological processes such as epigenetic regulation have important and far-reaching consequences. As this research shows, epigenetics offers both the potential to underpin new therapies in the future but also to help us to understand how the normal functioning of our bodies operates.”